The placebo effect plays a big role in clinical trials for mood disorders such as depression. Emory psychiatrist Andy Miller hit upon something several years ago that could unlock a path around the placebo effect.
Miller and his colleagues have been looking at the connection between inflammation and depression, whose evolutionary dimensions we have previously explored. They’ve examined the ability of inflammation-inducing treatments for hepatitis C and cancer to trigger symptoms of depression, and have shown that the anti-inflammatory drug infliximab (mainly used for rheumatoid arthritis) can resolve some cases of treatment-resistant depression. [Lots of praise for Miller in this September 2017 Nature Medicine feature.]
A recent paper in Psychotherapy and Psychosomatics from Miller and psychiatry chair Mark Rapaport looks at clinical trials testing an anti-inflammatory drug against psoriasis, to see whether participants’ depressive symptoms improved. This sidesteps a situation where doctors’ main targets are the patients’ moods.
When it comes to approving new antidepressants, the FDA is still probably going to want a frontal assault on depression, despite provisions in the 21st Century Cures Act to broaden the types of admissible evidence. Still, this line of research could clarify who could benefit from anti-inflammatory treatments and illuminate viable biomarkers and pathways.
The paper results from a collaboration with Eli Lilly. Lilly’s ixekizumab (commercial name: Taltz) is an antibody against the cytokine IL-17A, used to treat moderate to severe psoriasis. Taltz was approved by the FDA in 2016, after clinical trials published in the New England Journal of Medicine. Read more
Low estrogen levels may make women more susceptible to the development of post-traumatic stress disorder (PTSD) at some points in their menstrual cycles or lifetimes, while high estrogen levels may be protective.
New research from Emory University School of Medicine and Harvard Medical School provides insight into how estrogen changes gene activity in the brain to achieve its protective effects.
The findings, published in Molecular Psychiatry, could inform the design of preventive treatments aimed at reducing the risk of PTSD after someone is traumatized.
The scientists examined blood samples from 278 women from the Grady Trauma Project, a study of low-income Atlanta residents with high levels of exposure to violence and abuse. They analyzed maps of DNA methylation, a modification to the shape of DNA that is usually a sign of genes that are turned off.
The group included adult women of child-bearing age, in which estrogen rises and falls with the menstrual cycle, and women that had gone through menopause and had much lower estrogen levels.
“We knew that estrogen affects the activity of many genes throughout the genome,” says Alicia Smith, PhD, associate professor and vice chair of research in the Department of Gynecology and Obstetrics at Emory University School of Medicine. “But if you look at the estrogen-modulated sites that are also associated with PTSD, just one pops out.”
That site is located in a gene called HDAC4, known to be critical for learning and memory in mice. Genetic variation in HDAC4 among the women was linked to a lower level of HDAC4 gene activity and differences in their ability to respond to and recover from fear, and also differences in “resting state” brain imaging. Women with the same variation also showed stronger connections in activation between the amygdala and the cingulate cortex, two regions of the brain involved in fear learning. Read more
Happiness can be elusive, both in personal life and as a scientific concept. That’s why this paper, recently published in Molecular Psychiatry, seemed so striking.
“A genome-wide association study of positive emotion identifies a genetic variant and a role for microRNAs.” Translation: a glimpse into the genetics of positive emotions.
Editorial note: Although the research team here is careful and confirms the findings in independent groups and in brain imaging and fear discrimination experiments, this is a preliminary result. More needs to be explored about how these genetic variants and others affect positive emotions.
“With relatively few studies on genetic underpinnings of positive emotions, we face the challenges of a nascent research area,” the authors write.
Perhaps ironically, the finding comes out of the Grady Trauma Project, a study of inner-city residents exposed to high rates of abuse and violence, aimed at understanding mechanisms of resilience and vulnerability in depression and PTSD.
“Resilience is a multidimensional phenomenon, and we were looking at just one aspect of it,” says first author Aliza Wingo. She worked with Kerry Ressler , now at Harvard, and Tanja Jovanovic and other members of the Grady Trauma Project team.
“Positive affect” is what the team was measuring, through responses on questionnaires. And the questions are asking for the extent that respondents feel a particular positive emotion in general, rather than that day or that week. Read more
Emory researchers have identified molecular mechanisms that regulate motivation and persistence in mice. Their findings could have implications for intervention in conditions characterized by behavioral inflexibility, such as drug abuse and depression.
Scientists showedÂ that by manipulating a particular growth factor in one region of the brain, they couldÂ tune up or down a mouseâ€™s tendency to persist in seeking a reward. In humans, this region of the brain is located just behind the eyes and is called the medial orbitofrontal cortex or mOFC.
â€œWhen we make decisions, we often need to gauge the value of a reward before we can see it — for example, will lunch at a certain restaurant be better than lunch at another, or worth the cost,â€ says Shannon Gourley, PhD, assistant professor of pediatrics and psychiatry at Emory University School of Medicine. â€œWe think the mOFC is important for calculating value, particularly when we have to imagine the reward, as opposed to having it right in front of us.â€
The results were published WednesdayÂ inÂ Journal of Neuroscience.
Shannon Gourley, PhD
Being able to appropriately determine the value of a perceived reward is critical in goal-directed decision making, a component of drug-seeking and addiction-related behaviors. While scientists already suspected that the medial orbitofrontal cortex was important for this type of learning and decision-making, the specific genes and growth factors were not as well-understood.
The researchers focused on brain-derived neurotrophic factor (BDNF), a protein that supports the survival and growth of neurons in the brain. BDNF is known to play key roles in long-term potentiation and neuronal remodeling, both important in learning and memory tasks. Variations in the human gene that encodes BDNF have been linked with several psychiatric disorders.
Research on depression must deal with a major obstacle: the placebo effect. This is the observation that patients improve in response to the sugar pills given as controls in clinical studies.
Clinical trial designers can incorporate various clever strategies to minimize the placebo effect, which is actually comprised of severalÂ statistical and psychological factors. Investigators can try to enhance, dissect or even â€œharnessâ€ them. [A recent piece in the New York Times from Jo Marchant focuses on the placebo effect in studies of pain relief.]
Emory psychiatrist Andrew Miller and his team have been developing a different approach over the last few years: studying symptoms of depression in people who are being treated for something else. This allows them to sidestep, at least partially, the cultural construct of depression, from William Styron to Peter Kramer to direct-to-consumer television ads.
Interferon alpha, a treatment used against hepatitis C virus infection and some forms of cancer, is a protein produced by the immune system that spurs inflammation. It also can induce symptoms of depression, such as fatigue and malaise. There are some slight differences with psychiatric depression, which Millerâ€™s team describes here (less guilt!), but they conclude that there is a â€œhigh degree of overlap.â€
Miller and his colleagues, including Jennifer Felger and Ebrahim Haroon, have documented how interferon-alpha-induced inflammation affects the brains of hepatitis C and cancer patients in several papers. That research, in turn, informs their more recent fruitful investigations of inflammation in the context of major depression. More on that soon.
Violence and trauma are certainly not gifts, but scientifically, the Grady Trauma Project keeps on giving, even after co-director Kerry Resslerâ€™s 2015 move to Massachusetts. Research at Emory on the neurobiology of post-traumatic stress disorder (PTSD) continues. This Nature Communications paper, published in December with VA-based psychiatrist Aliza Wingo as lead author, is an example.
Three interesting things about this paper:
- The focus on PTSD co-occurring with depression. As the authors note, several studies looking at traumatized individuals found PTSD and depression together more often than they were present separately. This was true of Atlanta inner city residents in the Grady Trauma Project, veterans and survivors of the 2001 World Trade Center attack.
- DICER: the gene whose activity is turned down in blood samples from people with PTSD plus depression. Its name evokes one of the three Fates in Greek mythology, Atropos, who cuts the thread of life. DICER is at the center of a cellular network of regulation, because it is part of the machinery that generates regulatory micro-RNAs.
- The findings recapitulate work in mouse models of stress and its effects on the brain, with a connection to the many-tentacled Wnt signaling/adhesion protein beta-catenin.
Some past posts on the Grady Trauma Projectâ€™s scientific fruits follow. Read more
About one third of people with depression have high levels of inflammation markers in their blood. New research indicates that persistent inflammation affects the brain in ways that are connected with stubborn symptoms of depression, such as anhedonia, the inability to experience pleasure.
The results were published online on Nov. 10 inÂ Molecular Psychiatry.
The findings bolster the case that the high-inflammation form of depression is distinct, and are guiding researchersâ€™ plans to test treatments tailored for it.
Anhedonia is a core symptom of depression that is particularly difficult to treat, says lead author Jennifer Felger, PhD, assistant professor of psychiatry and behavioral sciences at Emory University School of Medicine and Winship Cancer Institute.
“Some patients taking antidepressants continue to suffer from anhedonia,” Felger says. “Our data suggest that by blocking inflammation or its effects on the brain, we may be able to reverse anhedonia and help depressed individuals who fail to respond to antidepressants.”
In a study of 48 patients with depression, high levels of the inflammatory marker CRP (C-reactive protein) were linked with a “failure to communicate”, seen through brain imaging, between regions of the brain important for motivation and reward.
Emory researchers have found that high inflammation in depression is linked to a “failure to communicate” between two parts of the brain: the ventral striatum (VS, vertical cross section) and the ventromedial prefrontal cortex (vmPFC, horizontal). Images from Felger et al, Molecular Psychiatry (2015).
Neuroscientists can infer that two regions of the brain talk to each other by watching whether they light up in magnetic resonance imaging at the same times or in the same patterns, even when someone is not doing anything in particular. They describe this as “functional connectivity.”
In 2013, Brian Dias (at Yerkes) and Kerry Ressler (now at Harvard) describedÂ a surprising example of epigenetic inheritance.
They found that a mouse, exposed to a smell in combination with stress, could transmit the resulting sensitivity to that smell to its offspring. At the time, there wasn’t a lot of information about mechanism.
Now other scientistsÂ haveÂ substantiatedÂ a proposal that micro RNA in playing a role in sperm. See this story (“Sperm RNAs transmit stress”) from Kate Yandell in The ScientistÂ or this one from Rachel Zamzow at Spectrum, the Simons Foundation’s autism news site, for more. An added wrinkle is that thisÂ research showsÂ that descendantsÂ of stress-exposed mice show a muted response to stress.
Note for Emory readers: Dias is scheduled to give a Frontiers in Neuroscience talk on Friday.
This intriguing research has received plenty of attention, Â both when it was presented at the Society of Neuroscience meeting in the fall and then when the results were published in Nature Neuroscience.
The short summary is: researchers at Yerkes National Primate Research Center found that when a mouse learns to become afraid of a certain odor, his or her pups will be more Gafas Ray Ban Baratas sensitive to that odor, even though the pups have never encountered it.Â Both the parent mouse and pups have more space in the smell-processing part of their brains, called the olfactory bulb, devoted to the odor to which they are sensitive.
[Note: a feature on a similar phenomenon, transgenerational inheritance of the effects of chemical exposure, appeared in Science this week]
Somehow information about the parent’s experiences is being inherited. But how? Brian Dias and Kerry Ressler are now pursuing followup experiments to firmly establish what’s going on. They discuss their research in this video: